Substituted tricyclic heterocycles as serotonin receptor agonists and antagonists

ABSTRACT

The present application describes compounds, including all pharmaceutically acceptable salts, prodrugs, solvates and stereoisomers thereof, according to Formula I, pharmaceutical compositions, comprising at least one compound according to Formula I and optionally at least one additional therapeutic agent and methods of treating various diseases, conditions and disorders associated with modulation of serotonin receptors such as, for example: metabolic diseases, which includes but is not limited to obesity, diabetes, diabetic complications, atherosclerosis, impared glucose tolerance and dyslipidemia; central nervous system diseases which includes but is not limited to, anxiety, depression, obsessive compulsive disorder, panic disorder, psychosis, schizophrenia, sleep disorder, sexual disorder and social phobias; cephalic pain; migraine; and gastrointestinal disorders using compounds according to Formula I

RELATED APPLICATION

This application claims priority benefit under Title 35 § 119(e) of U.S.Provisional Application No. 60/710,954, filed Aug. 24, 2005, thecontents of which are herein incorporated by reference.

BACKGROUND OF THE INVENTION

The neurotransmitter/hormone serotonin (5-hydroxytryptamine, 5-HT)regulates many physiological processes via a group of at least 14distinct receptors that are organized into 7 subfamilies (Hoyer, D., etal., Pharmacol. Rev., 46, 1994). The 5-HT₂ subfamily is composed of the5-HT_(2A), 5-HT_(2B), and 5-HT_(2C) receptors as determined by genehomology and pharmacological properties. There exists a substantialcorrelation for the relationship between 5-HT₂ receptor modulation and avariety of diseases and therapies. Prior to the early 1990's the5-HT_(2C) and 5-HT_(2A) receptors were referred to as 5-HT_(1C) and5-HT₂, respectively.

The direct or indirect agonism or antagonism of 5-HT₂ receptors, eitherselectively or non-selectively, has been associated with the treatmentof various central nervous system (CNS) disorders including obesity,depression, schizophrenia and bi-polar disorders. In the recent past thecontribution of serotonergic activity to the mode of action ofanti-obesity drugs has been well documented. Compounds that increase theoverall basal tone of serotonin in the CNS have been developed asanorectic drugs. The serotonin releasing agents, such as fenfluramine,function by increasing the amount of serotonin present in the nervesynapse. These breakthrough treatments, however, are not without sideeffects. Due to the mechanism of action of serotonin releasing agents,they effect the activity of a number of serotonin receptor subtypes in awide variety of organs including those not associated with the desiredmechanism of action. This non-specific modulation of the serotoninfamily of receptors most likely plays a significant role in the sideeffect profile. In addition, these compounds or their metabolites oftenhave a high affinity for a number of the serotonin receptors as well asa multitude of other monoamine neurotransmitters and nuisance receptors.Removing some of the receptor cross reactivity would allow for theexamination and possible development of potent therapeutic ligands withan improved side effect profile.

The 5-HT_(2C) receptor is a G-protein coupled receptor. It is almostexclusively expressed in the central nervous system including thehypothalamus, hippocampus, amygdala, nucleus of the solitary tract,spinal cord, cortex, olfactory bulb, ventral tegmental area (VTA),nucleus accumbens and choroid plexus (Hoffman, B. and Mezey, E., FEBSLett., 247, 1989). There is ample evidence to support the role ofselective 5-HT_(2C) receptor ligands in a number of disease therapies.5-HT_(2C) knockout mice develop a late stage obesity syndrome that isnot reversed by fenfluramine or other direct acting 5-HT_(2C) agonistssuch as mCPP (Nonogaki, K., et al., Nature Med., 4, 1998; Vickers, S.,et. al., Psychopharmacology, 143, 1999). Administration of selective5-HT_(2C) agonists to rats causes a reduction in food intake andcorresponding reduction in body weight (Vickers, S., et al., Br. J.Pharmacol., 130, 2000) and these responses can be blocked byadministration of selective 5-HT_(2C) antagonists (Vicker, S., et al.,Neuropharmacol., 41, 2001). 5-HT_(2C) receptor modulation in thehypothalamus can also influence thermoregulation (Mazzola-Pomietto, P,et al., Psychopharmacology, 123, 1996), sleep (Sharpley, A., et al.,Neuropharmacology, 33, 1994), sexual behavior and neuroendocrinefunction (Rittenhouse, P. et al., J. Pharmacol. Exp. Ther., 271, 1994).Activation of 5-HT_(2C) receptors in the VTA modulates the activity ofdopaminergic neurons that are involved in aspects of depression (DiMatteo, V. et al., Trends Pharmacol. Sci., 22, 2001) and 5-HT_(2C)receptor agonists such as WAY 161503, RO 60-0175 and RO 60-0332 areactive in rodent models of depression (Cryan, J. and Lucki, I., J.Pharmacol. Exp. Ther., 295, 2000). 5-HT_(2C) agonists have been reportedto reduce the rewarding effects of nicotine administration in rats(Grottick, A., et al., Psychopharmacology, 157, 2001) and influencesrodent responses to cocaine administration (Grottick, A., et al., J.Pharmacol. Exp. Ther., 295, 2000). Modulation of 5-HT_(2C) receptors inthe spinal cord can influence pain perception (Chojnacka-Wojcik, E., etal., Pol. J. Pharmacol., 46, 1994). There is also data indicating thatthe 5-HT_(2C) receptor agonists mCPP and RO 60-0175 mediate penileerections in rats (Millan, M., et al., Eur J. Pharmacol. 325, 1997).

DETAILED DESCRIPTION OF THE INVENTION

The present application describes compounds according to Formula I,pharmaceutical compositions, comprising at least one compound accordingto Formula I and optionally at least one additional therapeutic agentand methods of treating various diseases, conditions and disordersassociated with modulation of serotonin receptors such as, for example:metabolic diseases, which includes but is not limited to obesity,diabetes, diabetic complications, atherosclerosis, impared glucosetolerance and dyslipidemia; central nervous system diseases whichincludes but is not limited to, anxiety, depression, obsessivecompulsive disorder, panic disorder, psychosis, schizophrenia, sleepdisorder, sexual disorder and social phobias; cephalic pain; migraine;and gastrointestinal disorders using compounds according to Formula I

including all pharmaceutically acceptable salt forms, prodrugs, solvatesand stereoisomers thereof, wherein b, R¹, R², R³, R³, R⁴, R⁵, R⁶ and R⁷are described herein.

Definitions

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

Unless otherwise indicated, the term “alkyl” as employed herein alone oras part of another group includes both straight and branched chainhydrocarbons, containing 1 to 40 carbons, preferably 1 to 20 carbons,more preferably 1 to 6 carbons, in the normal chain, such as, forexample, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like.

Unless otherwise indicated, the term “alkenyl” as used herein by itselfor as part of another group refers to straight or branched chainradicals of 2 to 20 carbons, preferably 2 to 12 carbons, and morepreferably 2 to 6 carbons in the normal chain, which include one or moredouble bonds in the normal chain, such as, for example, vinyl,2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl,3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl,4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and thelike.

Unless otherwise indicated, the term “alkynyl” as used herein by itselfor as part of another group refers to straight or branched chainradicals of 2 to 20 carbons, preferably 2 to 12 carbons and morepreferably 2 to 8 carbons in the normal chain, which include one or moretriple bonds in the normal chain, such as, for example, 2-propynyl,3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl,2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the like.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine and iodine.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group refers to saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl andtricyclic alkyl, containing a total of 3 to 20 carbons forming therings, preferably 3 to 10 carbons, forming the ring such as, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl,

wherein the cycloalkyl may be fused to 1 aromatic ring as described foraryl.

The term “heterocyclyl”, as used herein, refers to an unsubstituted orsubstituted stable 4-, 5-, 6- or 7-membered monocyclic ring system whichmay be saturated or unsaturated, and which consists of carbon atoms andfrom one to four heteroatoms selected from N, O, S, SO and/or SO₂ group,wherein the nitrogen heteroatoms may optionally be oxidized, and thenitrogen heteroatom may optionally be quarternized. The heterocyclicring may be attached at any heteroatom or carbon atom which results inthe creation of a stable structure such as, for example, piperidinyl,piperazinyl, oxopiperazinyl, oxopiperidinyl and oxadiazolyl.

The term “aryl” as employed herein alone or as part of another grouprefers to monocyclic and bicyclic aromatic groups containing 6 to 10carbons in the ring portion such as, for example, phenyl or naphthyl andmay optionally include one to three additional rings fused to “aryl”such as, for example, aryl, cycloalkyl, heteroaryl or cycloheteroalkylrings.

The term “heteroaryl” as used herein refers to a 5-, 6- or 7-memberedaromatic heterocyclic ring which contains one or more heteroatomsselected from nitrogen, sulfur and oxygen. Such rings may be fused toanother ring such as, for example, cycloalkyl, cycloheteroalkyl, aryl orheteroaryl and include possible N-oxides.

The term “oxy” as used herein as part of another group refers to anoxygen atom serving as a linker between two groups such as, for example,hydroxy, oxyalkyl, oxyalkenyl, oxyalkynyl, oxyperfluoroalkyl, oxyaryl,oxyheteroaryl, oxycarboalkyl, oxycarboalkenyl, oxycarboalkynyl,oxycarboaryl, oxycarboheteroaryl, oxycarbocycloalkyl,oxycarboaminoalkyl, oxycarboaminoalkenyl, oxycarboaminoalkynyl,oxycarboaminoaryl, oxycarboaminocycloalkyl, oxycarboaminoheterocyclyl,oxycarboaminoheteroaryl, aminocarboxyalkyl, aminocarboxyalkenyl,aminocarboxyalkynyl, aminocarboxyaryl, aminocarboxycycloalkyl,aminocarboxyheterocyclyl and aminocarboxyheteroaryl,

The term “carbo” as used herein as part of another group refers to acarbonyl (C═O) group serving as a linker between two groups such as, forexample, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, carboxyaryl,carboxyheteroaryl, carboxycycloalkyl, oxycarboalkyl, oxycarboalkenyl,oxycarboalkynyl, oxycarboaryl, oxycarboheteroaryl, oxycarbocycloalkyl,carboaminoalkyl, carboaminoalkenyl, carboaminoakynyl, carboaminoaryl,carboaminocycloalkyl, carboheterocyclyl, carboheteroaryl,carboaminoheterocyclyl, carboaminoheteroaryl, aminocarboalkyl,aminocarboalkenyl, aminocarboalkynyl, aminocarboaryl,aminocarbocycloalkyl, aminocarboheterocyclyl, aminocarboheteroaryl,oxycarboaminoalkyl, oxycarboaminoalkenyl, oxycarboaminoalkynyl,oxycarboaminoaryl, oxycarboaminocycloalkyl, oxycarboaminoheterocyclyl,oxycarboaminoheteroaryl, aminocarboxyalkyl, aminocarboxyalkenyl,aminocarboxyalkynyl, aminocarboxyaryl, aminocarboxycycloalkyl,aminocarboxyheterocyclyl, aminocarboxyheteroaryl, aminocarboaminoalkyl,aminocarboaminoalkenyl, aminocarboaminoalkynyl, aminocarboaminoaryl,aminocarboaminocycloalkyl, aminocarboheterocyclyl, aminocarboheteroaryl,aminocarboaminoheterocyclyl and aminocarboaminoheteroaryl.

The term “thio” as used herein as part of another group refers to asulfur atom serving as a linker between two groups such as, for example,thioalkyl, thioalkenyl, thioalkynyl, thioaryl, thioheteroaryl,thiocycloalkyl and thioheterocyclyl.

The term “perfluoro” as used herein as part of another group refers to agroup wherein more than one hyrdogen atom attached to one or more carbonatoms in the group has been replaced with a fluorine atom such as, forexample, perfluoroalkyl, perfluoroalkenyl, perfluoroalkynyl andoxyperfluoroalkyl.

The term “amino” as used herein alone or as part of another group refersto a nitrogen atom that may be either terminal or a linker between twoother groups, wherein the group may be a primary, secondary or tertiary(two hydrogen atoms bonded to the nitrogen atom, one hydrogen atombonded to the nitrogen atom and no hydrogen atoms bonded to the nitrogenatom, respectively) amine such as, for example, amino, aminoalkyl,aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl, aminocycloalkyl,alkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino,cycloalkylamino, carboaminoalkyl, carboaminoalkenyl, carboaminoakynyl,carboaminoaryl, carboaminocycloalkyl, carboheterocyclyl,carboheteroaryl, carboaminoheterocyclyl, carboaminoheteroaryl,aminocarboalkyl, aminocarboalkenyl, aminocarboalkynyl, aminocarboaryl,aminocarbocycloalkyl, aminocarboheterocyclyl, aminocarboheteroaryl,oxycarboaminoalkyl, oxycarboaminoalkenyl, oxycarboaminoalkynyl,oxycarboaminoaryl, oxycarboaminocycloalkyl, oxycarboaminoheterocyclyl,oxycarboaminoheteroaryl, aminocarboxyalkyl, aminocarboxyalkenyl,aminocarboxyalkynyl, aminocarboxyaryl, aminocarboxycycloalkyl,aminocarboxyheterocyclyl, aminocarboxyheteroaryl, aminocarboaminoalkyl,aminocarboaminoalkenyl, aminocarboaminoalkynyl, aminocarboaminoaryl,aminocarboaminocycloalkyl, aminocarboheterocyclyl, aminocarboheteroaryl,aminocarboaminoheterocyclyl, aminocarboaminoheteroaryl, aminosulfoalkyl,aminosulfoalkenyl, aminosulfoalkynyl, aminosulfoaryl,aminosulfocycloalkyl, aminosulfoheterocyclyl, aminosulfoheteroaryl,aminosulfoalkylamino, aminosulfoalkenylamino, aminosulfoalkynylamino,aminosulfoarylamino, aminosulfocycloalkylamino,aminosulfoheterocyclylamino and aminosulfoheteroarylamino.

The term “nitrile” as used herein refers to a cyano (a carbon atomtriple-bonded to a nitrogen atom) group.

The term “sulfinyl” as used herein as part of another group refers to an—SO— group such as, for example, sulfinylalkyl, sulfinylalkenyl,sulfinylalkynyl, sulfinylaryl, sulfinylcycloalkyl, sulfinylheterocyclyl,sulfinylheteroaryl, sulfinylamino and sulfinylamido.

The term “sulfonyl” as used herein as part of another group refers to an—SO₂— group such as, for example, sulfonylalkyl, sulfonylalkenyl,sulfonylalkynyl, sulfonylaryl, sulfonylcycloalkyl, sulfonylheterocyclyland sulfonylheteroaryl.

An administration of a therapeutic agent of the application includesadministration of a therapeutically effective amount of the agent of theapplication. The term “therapeutically effective amount” as used hereinrefers to an amount of a therapeutic agent to treat or prevent acondition treatable by administration of a composition of theapplication. That amount is the amount sufficient to exhibit adetectable therapeutic or preventative or ameliorative effect. Theeffect may include, for example, treatment or prevention of theconditions listed herein. The precise effective amount for a subjectwill depend upon the subject's size and health, the nature and extent ofthe condition being treated, recommendations of the treating physician,and the therapeutics or combination of therapeutics selected foradministration. Thus, it is not useful to specify an exact effectiveamount in advance.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., the compound of formula I) is a prodrug within the scopeand spirit of the application.

The term “prodrug esters” as employed herein includes esters andcarbonates formed by reacting one or more hydroxyls of compounds offormula I with alkyl, alkoxy, or aryl substituted acylating agentsemploying procedures known to those skilled in the art to generateacetates, pivalates, methylcarbonates, benzoates and the like.

Various forms of prodrugs are well known in the art and are describedin:

a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch31, (Academic Press, 1996);

b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); and

c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson andH. Bundgaard, eds. Ch. 5, pgs 113-191 (Harwood Academic Publishers,1991). Said references are incorporated herein by reference.

All stereoisomers of the compounds of the instant application arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present application can have asymmetric centers atany of the carbon atoms including any one of the R substituents.Consequently, compounds of formula I can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic techniques or fractional crystallization.

The pharmaceutically acceptable salts of the compounds of formula I ofthe application include alkali metal salts such as lithium, sodium orpotassium, alkaline earth metal salts such as calcium or magnesium, aswell as zinc or aluminum and other cations such as ammonium, choline,diethanolamine, ethylenediamine, t-butylamine, t-octylamine,dehydroabietylamine, as well as pharmaceutically acceptable anions suchas chloride, bromide, iodide, tartrate, acetate, methanesulfonate,maleate, succinate, glutarate, stearate and salts of naturally occurringamino acids such as arginine, lysine, alanine and the like, and prodrugesters thereof.

Synthesis

Throughout the details of the applications, the following abbreviationsare used with the following meanings:

Reagents:

Et₃N triethylamine

TFA trifluoroacetic acid

LiAlH₄ lithium aluminum hydride

Solvents:

THF tetrahydrofuran

MeOH methanol

EtOH ethanol

EtOAc ethyl acetate

DMF dimethyl formamide

DMSO dimethyl sulfoxide

Et₂O diethylether

Others:

Ar aryl

Ph phenyl

Me methyl

Et ethyl

BOC tert-butoxycarbonyl

CBZ benzyloxycarbonyl

Bn benzyl

Bu butyl

Pr propyl

mL milliliter

mmol millimole

mg milligram

g gram

aq. aqueous

sat. saturated

The compounds of the present applications can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present applications can be synthesized using themethods described below, together with synthetic methods known in theart of synthetic organic chemistry, or variations thereon as appreciatedby those skilled in the art. Preferred methods include, but are notlimited to, those described below. All references cited herein arehereby incorporated in their entirety herein by reference.

The novel compounds of this applications may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagent and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the regents and reactions proposed.Such restrictions to the substituents which are compatible with thereaction conditions will be readily apparent to one skilled in the artand alternate methods must then be used.

The preparation of compounds of Formula (I) of the present applicationsmay be carried out in a convergent or sequential synthetic manner.Detailed synthetic preparations of the compounds of Formula (I) areshown in the following reaction schemes. The skills required inpreparation and purification of the compounds of Formula (I) and theintermediates leading to these compounds are known to those in the art.Purification procedures include, but are not limited to, normal orreverse phase chromatography, crystallization, and distillation.

Several methods for the preparation of the compounds of the presentapplications are illustrated in the schemes and examples shown below.The substitutions are as described and defined above.

Compounds of Formula (I) of this application may be prepared as shown inScheme 1. Thus, preparation of an aryl Grignard reagents (III) isaccomplished, for example, by treatment of a corresponding substitutedbromobenzene (II) with Mg. Formation of alkyl1-alkyl-3-arylpiperidine-4-carboxylate (V) is accomplished by additionof the arylmagnesium bromide (III) to the n-alkyl-tetrahydropyridineester (IV). Assembly of the core 3-aza-fluoren-9-one intermediate (VI)is accomplished by hydrolysis of ester (V) followed by cyclization inpolyphosphoric acid (see, for example, Paragamian, V. U.S. Pat. No.3,462,443, 1969; and Cook, C. E., et. al., J. Med. Chem. 1995, 38, 753).

The corresponding enantiomers can be isolated by separation of theracemic mixture of (VI) on a chiral stationary phase column utilizingnormal or reverse phase HPLC techniques. Alternatively, a diastereomericmixture of (VI) can be prepared by treatment of (VI) with an appropriatechiral acid (or suitably activated derivative), for example dibenzoyltartrate or the like (see, for example, Kinbara, K., et. al., J. Chem.Soc., Perkin Trans. 2, 1996, 2615; and Tomori, H., et. al., Bull. Chem.Soc. Jpn., 1996, 3581). The diastereomers would then be separated bytraditional techniques (i.e. silica chromatography, crystallization,HPLC, etc) followed by removal of the chiral auxiliary to affordenantiomerically pure (VI).

Highly functionalized aryl Grignard Reagents (VIII) can be also preparedas described in Scheme 2. Formation of the arylmagnesium halides (VIII,X=Br or I) may be accomplished through halogen-magnesium exchangereaction of aryl halides (VII, X=Br or I) with treatment ofalkylmagnesium bromide, for example EtMgBr, i-PrMgBr, etc. at lowtemperature (see, Knochel, P. et. al., Angew. Chem. Int. Ed. 2003, 42,4302).

The tricyclic core (VI) may be prepared in stereoselective manneraccording to Cook, C. E. et. al. U.S. Patent 2004/0147539 as shown inScheme 3. Thus, N-substituted tetrahydropyridine-4-carboxylic acid (IX)may be coupled with optically pure 1R or 1S-camphorsultam (X) to yieldthe enoylsultam (XI). The resulting optically pure enoylsultan (XI) mayreact with arylmagnesium halide (III) to give the corresponding1,4-adduct (XII) with diastereofacial selectivity. Assembly of theoptically pure core 3-aza-fluoren-9-one intermediate (VI) isaccomplished by hydrolysis of sultam (XII) followed by cyclization.

The preparation of compounds of Formula (I) with additional diversity offunctionalization is shown in Scheme 4. Reaction of the ketone (XIII)with alkyl lithium or alkyl magnesium halide followed by dehydration bytreatment with aqueous acid, such as HCl, H₂SO₄ or H₃PO₄, forms the9-alkyl-tetrahydro-3-aza-fluorene (XIV). The substitutedhexahydro-3-aza-fluorene (XV) is accomplished by hydrogenation of alkene(XIV) with appropriate catalyst, such as Pd—C. Direct reduction of thecarbonyl functionality of the tricyclic ketone (XIII) by Et₃SiH in TFAaffords the 3-aza-fluorene (XVI). 9-Hydroxy-hexahydro-3-aza-fluorene(XVII) is also accomplished by reduction of ketone with hydride.

The R¹ moiety of (XIII), (XV), (XVI) or (XVII) at the basic nitrogen canbe manipulated. Alkyl R¹ may be removed under a variety of conditions asdescribed in Greene, T. W., Wuts, P. G. W., “Protective Groups inOrganic Synthesis, 2nd Edition”, John Wiley and Sons, Inc., New York,pages 309-405, 1991. The free secondary amine could then be re-alkylatedwith a different R¹, for example, by treatment with a suitablysubstituted alkyl halide (R¹Cl, R¹Br or R¹I) and a base, such as Et₃N,K₂CO₃ or isopropyl-diethyl amine, to afford additional compounds of type(I), as described, for example, by Glennon, R. A., et. al., Med. Chem.Res., 1996, 197.

The preparation of compounds of Formula (I) with additional diversity offunctionalization of the aromatic ring of the tricycle is shown inScheme 5 and described here. Any 3-aza-fluorene with activated arylgroup such as haloaromatics, aryldiazonium and aryltriflate act asexcellent counterparts for a number of important synthetictransformations.

For example, Suzuki coupling protocol can be applied to the R⁶ position.For a review and leading references of palladium catalyzed crosscoupling reactions, see Miyaura, N., Suzuki, A., Chem. Rev., 1995, 2457.One such procedure entails treatment of the aryl bromide (XVIII) with afunctionalized boronic acid (XIX) in the presence of a catalytic Pd(0)species, such as Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂, Pd(OAc)₂, Pd₂(dba)₃ and asuitable ligand such as PPh₃, AsPh₃, etc., or other such Pd(0) catalyst,and a base such as Na₂CO₃, Ba(OH)₂ or Et₃N in a suitable solvent such asDMF, toluene, THF, DME or the like, to afford the biaryl 3-aza-fluorene(XX).

Alternatively, treatment of bromine derivative (XVIII) with a palladiumcatalyst such as Pd(PPh₃)₄ or Pd(PPh₃)₂Cl₂ and a suitable base, apreferred one being potassium acatate, in the presence of diboronpinacol ester (XXI) affords the aryl boronic ester (XXII). This boronicester can undergo Suzuki coupling directly with a wide variety ofcommercially available bromides (XIII) under typical Suzuki conditionsas described above to afford the 3-aza-fluorene (XX).

Similarly compounds wherein R⁴, R⁵, and R⁷ are bromide, iodide,triflates, and/or diazo derivatives may be prepared by the syntheticsequence exemplified in Scheme 1, (starting with the suitablyfunctionalized bromo-aryl magnesium halides (III)). These compounds maybe coupled with a variety of boronic acids as described above in Scheme5, to afford the corresponding adducts (XXV). (see Miyaura, N., Suzuki,A., Chem. Rev., 1995, 2457, for a review of aryl couplings).

In addition, there exists a wide range of procedures and protocols forfunctionalizing haloaromatics, aryldiazonium and aryltriflate compounds.These procedures are well known by those in the art and described, forexample (see Stanforth, S. P., Tetrahedron, 1998, 263; Buchwald, S. L.,et. al., J. Am. Chem. Soc., 1998, 9722; Stille, J. K., et. al., J. Am.Chem. Soc., 1984, 7500). Among these procedures are biaryl couplings,alkylations, acylations, aminations, and amidations. The power ofpalladium catalyzed functionalization of aromatic cores has beenexplored in depth in the last decade. An excellent review of this fieldcan be found in J. Tsuji, “Palladium Reagents and Catalysts, Innovationsin Organic Synthesis”, J. Wiley and Sons, New York, 1995.

One example is described in Scheme 6, where the aromatic ring of Formula(I) is substituted with an arylamino group. Treatment of arylbromidederivatives of type (XIX) with diphenylmethyl imine in the presence of aPd(0) catalyst, such as Pd₂(dba)₃, Pd(PPh₃)₄ or Pd(PPh₃)₂Cl₂, andsuitable ligand such BINAP or PPh₃, and a base such as NaOtBu in asuitable solvent such as DMF, toluene, THF, DME, or the like, affords animine intermediate. Basic hydrolysis (hydroxylamine, sodium acetate inmethanol) affords the primary aniline derivative (XXVI). Coupling ofthese anilines with various arylbromide (XXIII) under Pd(0) catalyzedcondition described above affords the biaryl anilines (XXVII). Theprotocol described in Scheme 6 can also be applied to analogs of (XIX)where the R⁴, R⁵ or R⁷ groups are Br, I, OTf, etc., to afford analogs of(XXVII) where the arylamino group is on the R⁴, R⁵ or R⁷ position.

An alternate method for preparing secondary anilines (XXVIII) proceedsfrom bromides (XIX). Treatment of bromide (XVI) with a variety of alkylor benzylamines (XXVII), which can be chiral if R^(a) and R^(b) aredifferent groups, in the presence of a Pd(0) catalyst, such asPd₂(dba)₃, Pd(PPh₃)₄ or Pd(PPh₃)₂Cl₂, and suitable ligand such BINAP orPPh₃, and a base such as NaOtBu in a suitable solvent such as DMF,toluene, THF, DME, or the like, affords the secondary anilines (XXVIII).The protocol described in Scheme 7 can also be applied to analogs of(XIX) where the R⁴, R⁵ or R⁷ groups are Br, I, OTf, etc., to affordanalogs of (XXVIII) where the substituted amino group is on the R⁴, R⁵or R⁷ position.

An alternate method for preparing alkyl substituted 3-aza-fluorene (XXX)proceeds from bromides (XIX) and is shown in Scheme 8. Treatment ofbromide (XVI) with a variety of alkyl zinc chloride or dialkyl zinc inthe presence of a Pd(0) catalyst, such as Pd(dppf)Cl₂, Pd₂(dba)₃,Pd(PPh₃)₄ or Pd(PPh₃)₂Cl₂, and a base such as K₂CO₃ in a suitablesolvent such as DMF, toluene, THF, DME, or the like, affords the alkylsubstituted 3-aza-fluorene (XXX). The protocol described in Scheme 8 canalso be applied to analogs of (XIX) where the R⁴, R⁵ or R⁷ groups areBr, I, OTf, etc., to afford analogs of (XXX) where the substituted aminogroup is on the R⁴, R⁵ or R⁷ position.

In addition, derivatives of type (I) can be alkylated with any number offunctionalized alkyl sidechains. Typical procedures utilizing standardalkylation of a secondary amine with an alkylhalide under base catalyzedconditions are well known by those skilled in the art. For example, thesecondary amino group of Formula (I) (R¹=H) can be alkylated withalkylhalides or alkylsulfonates in the presence of NaI or KI and a basesuch as K₂CO₃, Na₂CO₃, triethylamine, or the like, in dioxane or THF orother such solvent while heating (see Glennon, R. A., et. al., Med.Chem. Res., 1996, 197) affords the R¹ alkylated indolines.

It is understood that the compounds of the present applications can beprepared in a number of ways well known to one skilled in the art oforganic synthesis. The compounds of the present applications can besynthesized using the methods described herein, together with syntheticmethods known in the art of synthetic organic chemistry, or variationsthereon as appreciated by those skilled in the art.

Utilities and Combinations

Utilities

The compounds of the present application are 5HT modulators, and includecompounds which are, for example, selective agonists, partial agonists,antagonists or partial antagonists of the 5HT_(2C) receptor.Accordingly, the compounds of the present application may be useful forthe treatment or prevention of diseases and disorders associated with5HT receptor activity. Preferably, compounds of the present applicationpossess activity as agonists of the 5HT_(2C) receptor, and may be usedin the treatment of diseases or disorders associated with the activityof the 5HT_(2C) receptor.

Accordingly, the compounds of the present application can beadministered for the treatment of a variety of conditions and disorders,including, but not limited to metabolic and eating disorders as well asconditions associated with metabolic disorders, (e.g., obesity,diabetes, arteriosclerosis, hypertension, polycystic ovary disease,cardiovascular disease, osteoarthritis, dermatological disorders,impaired glucose hemostatsis, insulin resistance, hypercholesterolemia,hypertriglyceridemia, cholelithiasis and sleep disorders, dislipidemicconditions, bulimia nervosa and compulsive eating disorders); pain;sleep disorders and psychiatric disorders, such as substance abuse,depression, anxiety, psychosis, mania and schizophrenia.

These compounds could also be used for the improvement of cognitivefunction (e.g., the treatment of dementia, including Alzheimer'sdisease, short term memory loss and attention deficit disorders);neurodegenerative disorders (e.g., Parkinson's Disease, cerebralapoplexy and craniocerebral trauma) and hypotension (e.g., hemorrhagicand endotoxin-induced hypotension). These compounds could also be usedfor treatment of cardiac dysfunction (e.g., associated with valvulardisease, myocardial infarction, cardiac hypertrophy or congestive heartfailure); and improvement of the overall pulmonary function; transplantrejection; rheumatoid arthritis; osteoarthritis; fibromyalgia; multiplesclerosis; inflammatory bowel disease; lupus; graft vs. host disease;T-cell mediated hypersensitivity disease; psoriasis; asthma; Hashimoto'sthyroiditis; Guillain-Barre syndrome; cancer; contact dermatitis;allergic rhinitis; and ischemic or reperfusion injury. These compoundscould also be used for treatment of sexual dysfunction anderectogenesis.

Compounds useful in the treatment of appetite or motivational disordersregulate desires to consume sugars, carbohydrates, alcohol or drugs andmore generally to regulate the consumption of ingredients with hedonicvalue. In the present description and in the claims, appetite disordersare understood as meaning: disorders associated with a substance andespecially abuse of a substance and/or dependency on a substance,disorders of eating behaviors, especially those liable to cause excessweight, irrespective of its origin, for example: bulimia nervosa,craving for sugars. The present application therefore further relates tothe use of a 5HT_(2C) receptor agonist for the treatment of bulimia andobesity, including obesity associated with type II diabetes(non-insulin-dependent diabetes), or more generally any diseaseresulting in the patient becoming overweight. It may be due to anycause, whether genetic or environmental, including overeating andbulemia, polycycstic ovary disease, craniopharyngeoma, Prader-WilliSyndrome, Frohlich's Syndrome, Type II diabetes, growth hormonedeficiency, Turner's Syndrome and other pathological statescharacterized by reduced metabolic activity or reduced energyexpenditure. As used with reference to the utilities described herein,the term “treating” or “treatment” encompasses prevention, partialalleviation, or cure of the disease or disorder. Further, treatment ofobesity is expected to prevent progression of medical covariants ofobesity, such as arteriosclerosis, Type II diabetes, polycystic ovarydisease, cardiovascular disease, osteoarthritis, dermatologicaldisorders, hypertension, insulin resistance, hypercholesterolemia,hypertriglyceridemia, cholelithiasis and sleep disorders.

Compounds in the present application may also be useful in treatingsubstance abuse disorders, including substance dependence or abusewithout physiological dependence. Substances of abuse include alcohol,amphetamines (or amphetamine-like substances), caffeine, cannabis,cocaine, hallucinogens, inhalents, nicotine, opioids, phencyclidine (orphencyclidine-like compounds), sedative-hypnotics or benzodiazepines,and other (or unknown) substances and combinations of the above. Theterms “substance abuse disorders” also includes drug, nicotine oralcohol withdrawal syndromes and substance-induced anxiety or mooddisorder with onset during withdrawal.

Compounds in the present application may be useful in treating memoryimpairment and cognitive disorders. The condition of memory impairmentis manifested by impairment of the ability to learn new informationand/or the inability to recall previously learned information. Memoryimpairment is a primary symptom of dementia and can also be a symptomassociated with such diseases as Alzheimer's disease, schizophrenia,Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeld-Jakob disease, attention deficit-hyperactivity disorder, HIV,cardiovascular disease such as ischemia or stroke, and head trauma aswell as age-related cognitive decline. Dementias are diseases thatinclude memory loss and additional intellectual impairment separate frommemory. 5HT_(2C) modulators may also be useful in treating cognitiveimpairments related to attentional deficits, such as attentiondeficit-hyperactivity disorders.

Compounds in the present application may also be useful in treatingdiseases associated with dysfunction of brain dopaminergic systems, suchas Parkinson's Disease and substance abuse disorders. Parkinsons'sDisease is a neurodenerative movement disorder characterized bybradykinesia and tremor.

Combinations

The present application includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present application can be used alone, in combinationwith other suitable therapeutic agents useful in the treatment of theaforementioned disorders including: anti-obesity agents; anti-diabeticagents, appetite suppressants; cholesterol/lipid-lowering agents,cognition enhancing agents, agents used to treat neurodegeneration,agents used to treat respiratory conditions, agents used to treat boweldisorders, anti-inflammatory agents; anti-anxiety agents;anti-depressants; anti-psychotic agents; sedatives; hypnotics;anti-hypertensive agents; anti-tumor agents and analgesics.

Such other therapeutic agent(s) may be administered prior to,simultaneously with, or following the administration of the 5HT_(2C)modulators in accordance with the application.

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present application include leptin andleptin-sensitizing agents, melanocortin receptor (MC4R) agonists,agouti-related peptide (AGRP) antagonists, melanin-concentrating hormonereceptor (MCHR) antagonists, growth hormone secretagogue receptor (GHSR)antagonists, orexin antagonists, CCK agonists, GLP-1 agonists, NPY1 orNPY5 antagonsits, NPY2 modulators, corticotropin releasing factoragonists, histamine receptor-3 (H3) modulators, aP2 inhibitors, PPARgamma modulators, PPAR delta modulators, beta 3 adrenergic agonists,such as AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer)or other known beta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204,5,770,615, 5,491,134, 5,776,983 and 5,488,064, a thyroid receptor betamodulator, such as a thyroid receptor ligand as disclosed in WO 97/21993(U. Cal SF), WO 99/00353 (KaroBio) and WO 00/039077 (KaroBio), a lipaseinhibitor, such as orlistat or ATL-962 (Alizyme), leptinergics,adiponectin modulating agents, cannabinoid-1 receptor antagonists, suchas SR-141716 (Sanofi) or SLV-319 (Solvay), acetyl CoA carboxylase (ACC)inhibitors as disclosed in International patent application WO 03/072197and monoamine reuptake inhibitors or releasing agents, such asfenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine,sertraline, chlorphentermine, cloforex, clortermine, picilorex,sibutramine, dexamphetamine, phentermine, phenylpropanolamine ormazindol, anorectic agents such as topiramate (Johnson & Johnson),axokine (Regeneron).

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present application include: insulin, which mayinclude short- and long-lasting forms as well as oral and inhaled forms,insulin secretagogues or insulin sensitizers, which may includebiguanides, sulfonyl ureas, glucosidase inhibitors, aldose reductaseinhibitors, PPAR γ agonists such as thiazolidinediones, PPAR α agonists(such as fibric acid derivatives), PPAR δ antagonists or agonists, PPARα/γ dual agonists such as muraglitizar described in Bristol-Myers SquibbU.S. Pat. No. 6,414,002, dipeptidyl peptidase IV (DPP4) inhibitors suchas saxagliptin described in Bristol-Myers Squibb U.S. Pat. Nos.6,395,767 and 6,573,287, SGLT2 inhibitors such as the compoundsdescribed in Bristol-Myers Squibb U.S. Pat. Nos. 6,414,126 and6,515,117, glycogen phosphorylase inhibitors, and/or meglitinides, aswell as insulin, and/or glucagon-like peptide-1 receptor agonist, and/ora PTP-1B inhibitor (protein tyrosine phosphatase-1B inhibitor).

The antidiabetic agent may be glucokinase inhibitors, 11 β HSDinhibitors or oral antihyperglycemic agents, which is preferably abiguanide such as metformin or phenformin or salts thereof, preferablymetformin HCl. Where the antidiabetic agent is a biguanide, thecompounds of the present application will be employed in a weight ratioto biguanide within the range from about 0.001:1 to about 10:1,preferably from about 0.01:1 to about 5:1.

The antidiabetic agent may also preferably be a sulfonyl urea such asglyburide (also known as glibenclamide), glimepiride (disclosed in U.S.Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, otherknown sulfonylureas or other antihyperglycemic agents which act on theATP-dependent channel of the beta-cells, with glyburide and glipizidebeing preferred, which may be administered in the same or in separateoral dosage forms. The oral antidiabetic agent may also be a glucosidaseinhibitor such as acarbose (disclosed in U.S. Pat. No. 4,904,769) ormiglitol (disclosed in U.S. Pat. No. 4,639,436), which may beadministered in the same or in a separate oral dosage forms.

The compounds of the present application may be employed in combinationwith a PPAR γ agonist such as a thiazolidinedione oralanti-diabetic-agent or other insulin sensitizers (which has an insulinsensitivity effect in NIDDM patients) such as troglitazone(Warner-Lambert's REZULIN, disclosed in U.S. Pat. No. 4,572,912),rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi's MCC-555(disclosed in U.S. Pat. No. 5,594,016), Glaxo-Wellcome's GL-262570,englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer,isaglitazone (MIT/J&J), JTT-501 (JPNT/P&U), L-895645 (Merck), R-119702(Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi), preferablyrosiglitazone and pioglitazone.

The compounds of the present application may be employed in combinationwith anti-hyperlipidemia agents, or agents used to treatarteriosclerosis. An example of an hypolipidemic agent would be an HMGCoA reductase inhibitor which includes, but is not limited to,mevastatin and related compounds as disclosed in U.S. Pat. No.3,983,140, lovastatin (mevinolin) and related compounds as disclosed inU.S. Pat. No. 4,231,938, pravastatin and related compounds such asdisclosed in U.S. Pat. No. 4,346,227, simvastatin and related compoundsas disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoAreductase inhibitors which may be employed herein include, but are notlimited to, fluvastatin, disclosed in U.S. Pat. No. 5,354,772,cerivastatin disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080,atorvastatin disclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929and 5,686,104, pitavastatin (Nissan/Sankyo's nisvastatin (NK-104) oritavastatin), disclosed in U.S. Pat. No. 5,011,930,Shionogi-Astra/Zeneca rosuvastatin (visastatin (ZD-4522)) disclosed inU.S. Pat. No. 5,260,440, and related statin compounds disclosed in U.S.Pat. No. 5,753,675.

The squalene synthetase inhibitors suitable for use herein include, butare not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No.5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol.31, No. 10, pp 1869-1871, including isoprenoid(phosphinyl-methyl)phosphonates as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. Nos.4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2-,1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293,phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987,109, 5544, cyclopropanes reported by Capson, T. L., PhD dissertation,June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp16, 17, 40-43, 48-51, Summary, pyrrolidine derivatives as disclosed bySasyou, et al, WO 02/083636 and N-aryl-substituted cyclic aminederivatives disclosed by Okada et al, WO 02/076973.

Other hypolipidemic agents suitable for use herein include, but are notlimited to, fibric acid derivatives, α PPAR agonists, such asfenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate,clinofibrate and the like, probucol, and related compounds as disclosedin U.S. Pat. No. 3,674,836, probucol, phenylfibrate and gemfibrozilbeing preferred, bile acid sequestrants such as cholestyramine,colestipol and DEAE-Sephadex (SECHOLEX, POLICEXIDE) and cholestagel(Sankyo/Geltex), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (anN-substituted ethanolamine derivative), imanixil (HOE-402),tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (SPC, Roche),aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulenederivative), melinamide (Sumitomo), Sandoz 58-035, American CyanamidCL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinicacid (niacin), acipimox, acifran, neomycin, p-aminosalicylic acid,aspirin, poly(diallylmethylamine) derivatives such as disclosed in U.S.Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammoniumchloride) and ionenes such as disclosed in U.S. Pat. No. 4,027,009, andother known serum cholesterol lowering agents.

The other hypolipidemic agent may be an ACAT inhibitor (which also hasanti-atherosclerosis activity) such as disclosed in, Drugs of the Future24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor, C1-1011 is effectivein the prevention and regression of aortic fatty streak area inhamsters”, Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998),137(1), 77-85; “The pharmacological profile of FCE 27677: a novel ACATinhibitor with potent hypolipidemic activity mediated by selectivesuppression of the hepatic secretion of ApoB100-containing lipoprotein”,Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; “RP73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor”,Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; “ACATinhibitors: physiologic mechanisms for hypolipidemic andanti-atherosclerotic activities in experimental animals”, Krause et al,Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, BocaRaton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”,Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; “Inhibitors ofacyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemicagents. 6. The first water-soluble ACAT inhibitor with lipid-regulatingactivity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7.Development of a series of substitutedN-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhancedhypocholesterolemic activity”, Stout et al, Chemtracts: Org. Chem.(1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd), as wellas F-1394, CS-505, F-12511, HL-004, K-10085 and YIC-C8-434.

The hypolipidemic agent may be an upregulator of LDL receptor activitysuch as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's SCH48461 (ezetimibe) as well as thosedisclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973(1998).

The other lipid agent or lipid-modulating agent may be a cholesteryltransfer protein inhibitor (CETP) such as Pfizer's Torcetrapib® as wellas those disclosed in WO/0038722 and in EP 818448 (Bayer) and EP 992496,and Pharmacia's SC-744 and SC-795, as well as CETi-1 and JTT-705.

The hypolipidemic agent may be an ileal Na⁺/bile acid cotransporterinhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).The ATP citrate lyase inhibitor which may be employed in the combinationof the application may include, for example, those disclosed in U.S.Pat. No. 5,447,954.

The other lipid agent also includes a phytoestrogen compound such asdisclosed in WO 00/30665 including isolated soy bean protein, soyprotein concentrate or soy flour as well as an isoflavone such asgenistein, daidzein, glycitein or equol, or phytosterols, phytostanol ortocotrienol as disclosed in WO 2000/015201; a beta-lactam cholesterolabsorption inhibitor such as disclosed in EP 675714; an HDL upregulatorsuch as an LXR agonist, a PPAR α-agonist and/or an FXR agonist; an LDLcatabolism promoter such as disclosed in EP 1022272; a sodium-protonexchange inhibitor such as disclosed in DE 19622222; an LDL-receptorinducer or a steroidal glycoside such as disclosed in U.S. Pat. No.5,698,527 and GB 2304106; an anti-oxidant such as beta-carotene,ascorbic acid, α-tocopherol or retinol as disclosed in WO 94/15592 aswell as Vitamin C and an antihomocysteine agent such as folic acid, afolate, Vitamin B6, Vitamin B12 and Vitamin E; isoniazid as disclosed inWO 97/35576; a cholesterol absorption inhibitor, an HMG-CoA synthaseinhibitor, or a lanosterol demethylase inhibitor as disclosed in WO97/48701; a PPAR δ agonist for treating dyslipidemia; or a sterolregulating element binding protein-I (SREBP-1) as disclosed in WO2000/050574, for example, a sphingolipid, such as ceramide, or neutralsphingomyelenase (N-SMase) or fragment thereof, and inhibitors or lipidsynthesis enzymes such as, for example, ACC, FAS, DGAT, MGAT, GPAT, AMPkinase, CPT1 and SCD1. Preferred dyslipidemic agents are pravastatin,lovastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin,rosuvastatin, ezetimibe, fenofibrate and Pfizer's Torcetrapib® as wellas niacin and/or cholestagel.

The compounds of the present application may be employed in combinationwith anti-hypertensive agents. Examples of suitable anti-hypertensiveagents for use in combination with the compounds of the presentapplication include beta adrenergic blockers, calcium channel blockers(L-type and T-type; e.g. diltiazem, verapamil, nifedipine, amlodipineand mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide,flumethiazide, hydroflumethiazide, bendroflumethiazide,methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide,ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine,bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors,ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril,ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril,lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan,valsartan, candasartan and talmisartan), ET receptor antagonists (e.g.,sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos.5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compoundsdisclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors,vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilatand gemopatrilat), and nitrates.

5HT_(2C) modulators could be useful in treating other diseasesassociated with obesity, including sleep disorders. Therefore, thecompounds described in the present application could be used incombination with therapeutics for treating sleep disorders. Examples ofsuitable therapies for treatment of sleeping disorders for use incombination with the compounds of the present application includemelatonin analogs, melatonin receptor agonists, ML 1 B agonists. GABA Areceptor agonists such as barbiturates (e.g., amobarbital, aprobarbital,butabarbital, mephobarbital, pentobarbital, phenobarbital, secobarbitaland talbutal), benzodiazepines (e.g., diazepam, lorazepam, oxazepam,alprazolam, chlordiazepoxide, clonazepam, chlorazepate, halazepam andprazepam), also specifically including triazolam (Halcion). Other agentsfor treating sleep disorders include zolpidem (Ambien) and Neurocrine'sindiplon.

5HT_(2C) modulators may reduce or ameliorate substance abuse oraddictive disorders. Therefore, combination of 5HT_(2C) modulators withagents used to treat addictive disorders may reduce the dose requirementor improve the efficacy of current addictive disorder therapeutics.Examples of agents used to treat substance abuse or addictive disordersare: selective serotonin reuptake inhibitors (SSRI), methadone,buprenorphine, nicotine and bupropion and opiate antagonists.

5HT_(2C) modulators may reduce anxiety or depression; therefore, thecompounds described in this application may be used in combination withanti-anxiety agents or antidepressants. Examples of suitableanti-anxiety agents for use in combination with the compounds of thepresent application include benzodiazepines (e.g., diazepam, lorazepam,oxazepam, alprazolam, chlordiazepoxide, clonazepam, chlorazepate,halazepam and prazepam), 5HT_(1A) receptor agonists (e.g., buspirone,flesinoxan, gepirone, ipsapirone and serzone), corticotropin releasingfactor (CRF) antagonists and SSRI's.

Examples of suitable classes of anti-depressants for use in combinationwith the compounds of the present application include norepinephrinereuptake inhibitors (tertiary and secondary amine tricyclics), selectiveserotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine,paroxetine, citalopram and sertraline), monoamine oxidase inhibitors(MAOIs) (isocarboxazid, phenelzine, tranylcypromine, selegiline),reversible inhibitors of monoamine oxidase (RIMAs) (moclobemide),serotonin and norepinephrine reuptake inhibitors (SNRIs) (venlafaxine),corticotropin releasing factor (CRF) receptor antagonists (Britsol-MyersSquibb U.S. Pat. Nos. 6,642,230; 6,630,476; 6,589,952; 6,579,876;6,525,056; 6,521,636; 6,518,271; 6,515,005; 6,448,261; 6,399,609;6,362,180; and 6,358,950), alpha-adrenoreceptor antagonists, andatypical antidepressants (bupropion, lithium, nefazodone, trazodone andviloxazine).

The combination of a conventional antipsychotic drug with a 5HT_(2C)modulator could also enhance symptom reduction in the treatment ofpsychosis or mania. Further, such a combination could enable rapidsymptom reduction, reducing the need for chronic treatment withantipsychotic agents. Such a combination could also reduce the effectiveantipsychotic dose requirement, resulting in reduced probability ofdeveloping the motor dysfunction typical of chronic antipsychotictreatment.

Examples of suitable antipsychotic agents for use in combination withthe compounds of the present application include the phenothiazine(chlorpromazine, mesoridazine, thioridazine, acetophenazine,fluphenazine, perphenazine and trifluoperazine), thioxanthine(chlorprothixene, thiothixene), heterocyclic dibenzazepine (clozapine,olanzepine and aripiprazole), butyrophenone (haloperidol),diphenylbutylpiperidine (pimozide) and indolone (molindolone) classes ofantipsychotic agents. Other antipsychotic agents with potentialtherapeutic value in combination with the compounds in the presentapplication include loxapine, sulpiride and risperidone.

Combination of the compounds in the present application withconventional antipsychotic drugs could also provide an enhancedtherapeutic effect for the treatment of schizophrenic disorders, asdescribed above for manic disorders. As used here, schizophrenicdisorders include paranoid, disorganized, catatonic, undifferentiatedand residual schizophrenia, schizophreniform disorder, schizoaffectivedisorder, delusional disorder, brief psychotic disorder and psychoticdisorder not specified. Examples of suitable antipsychotic drugs forcombination with the compounds in the present application include theantipsychotics mentioned above, as well as dopamine receptorantagonists, muscarinic receptor agonists, 5HT_(2A) receptor antagonistsand 5HT_(2A)/dopamine receptor antagonists or partial agonists (e.g.,olanzepine, aripiprazole, risperidone, ziprasidone).

The compounds described in the present application could be used toenhance the effects of cognition-enhancing agents, such asacetylcholinesterase inhibitors (e.g., tacrine the active agent inCognex®), ADHD agents (e.g. methyl-phenidate, atomoxetine the activeagent in Strattera® and histamine 3 antagonists), muscarinic receptor-1agonists (e.g., milameline), nicotinic agonists, glutamic acid receptor(AMPA and NMDA) modulators such as memantine, and nootropic agents(e.g., piracetam, levetiracetam). Examples of suitable therapies fortreatment of Alzheimer's disease and cognitive disorders for use incombination with the compounds of the present application includedonepezil, tacrine, revastigraine, 5HT6 receptor antagonists, gammasecretase inhibitors, beta secretase inhibitors, SK channel blockers,Maxi-K blockers, and KCNQs blockers.

The compounds described in the present application could be used toenhance the effects of agents used in the treatment of Parkinson'sDisease. Examples of agents used to treat Parkinson's Disease include:levadopa with or without a COMT inhibitor, antiglutamatergic drugs(amantadine, riluzole), alpha-2 adrenergic antagonists such as idazoxan,opiate antagonists, such as naltrexone, other dopamine agonists ortransportor modulators, such as ropinirole, or pramipexole orneurotrophic factors such as glial derived neurotrophic factor (GDNF).

The compounds described in the present application could be used incombination with agents used to treat erectile dysfunction. Examples ofsuitable treatment for erectile dysfunction include sildenafil (Viagra),vardenafil (Levitra) and tadalafil (Cialis). Other compounds that couldbe used in combination for erectile dysfunction include yohimbine,phentolamine and papaverine.

The compounds described in the present application could be used incombination with suitable anti-inflammatory agents. Examples of suitableanti-inflammatory agents for use in combination with the compounds ofthe present application include prednisone, dexamethasone,cyclooxygenase inhibitors (i.e., COX-1 and/or COX-2 inhibitors such asNSAIDs, aspirin, indomethacin, ibuprofen, piroxicam, Naproxen®,Celebrex®, Vioxx®, Arcoxia®, and Bextra®), CTLA4-Igagonists/antagonists, CD40 ligand antagonists, IMPDH inhibitors, such asmycophenolate (CellCept®), integrin antagonists, alpha-4 beta-7 integrinantagonists, cell adhesion inhibitors, interferon gamma antagonists,ICAM-1 inhibitor, tumor necrosis factor (TNF) antagonists (e.g.,infliximab, OR1384, including TNF-alpha inhibitors, such as tenidap,anti-TNF antibodies or soluble TNF receptor such as etanercept(Enbrel®), Remicade®, rapamycin (sirolimus or Rapamune) and leflunomide(Arava)), prostaglandin synthesis inhibitors, budesonide, clofazimine,CNI-1493, CD4 antagonists (e.g., priliximab), p38 mitogen-activatedprotein kinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKKinhibitors, and therapies for the treatment of irritable bowel syndrome(e.g., Zelnorm® and Maxi-K® openers such as those disclosed in U.S. Pat.No. 6,184,231 B1).

Exemplary of such other therapeutic agents which may be used incombination with 5HT_(2C) modulators include the following: cyclosporins(e.g., cyclosporin A), anti-IL-2 receptor (Anti-Tac), anti-CD45RB,anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonalantibody OKT3, agents blocking the interaction between CD40 and gp39,such as antibodies specific for CD40 and/or gp39 (i.e., CD154), fusionproteins constructed from CD40 and gp39 (CD40Ig and CD8gp39),inhibitors, such as nuclear translocation inhibitors, of NF-kappa Bfunction, such as deoxyspergualin (DSG), gold compounds,antiproliferative agents such as methotrexate, FK506 (tacrolimus,Prograf), mycophenolate mofetil, cytotoxic drugs such as azathiprine andcyclophosphamide, anticytokines such as antiIL-4 or IL-4 receptor fusionproteins and PDE 4 inhibitors such as Ariflo, and the PTK inhibitorsdisclosed in the following U.S. patent applications, incorporated hereinby reference in their entirety: Ser. No. 09/097,338, filed Jun. 15,1998; Ser. No. 09/094,797, filed Jun. 15, 1998; Ser. No. 09/173,413,filed Oct. 15, 1998; and Ser. No. 09/262,525, filed Mar. 4, 1999. Seealso the following documents and references cited therein andincorporated herein by reference: Hollenbaugh, D., Et Al, “CleavableCD40Ig Fusion Proteins and the Binding to Sgp39”, J. Immunol. Methods(Netherlands), 188(1), pp. 1-7 (Dec. 15, 1995); Hollenbaugh, D., et al,“The Human T Cell Antigen Gp39, A Member of the TNF Gene Family, Is aLigand for the CD40 Receptor: Expression of a Soluble Form of Gp39 withB Cell Co-Stimulatory Activity”, EMBO J (England), 11(12), pp. 4313-4321(December 1992); and Moreland, L. W. et al., “Treatment of RheumatoidArthritis with a Recombinant Human Tumor Necrosis Factor Receptor(P75)-Fc Fusion Protein,” New England J. of Medicine, 337(3), pp.141-147 (1997).

The above other therapeutic agents, when employed in combination withthe compounds of the present application, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

The compounds of formula I of the application can be administered orallyor parenterally, such as subcutaneously or intravenously, as well as bynasal application, transdermally, rectally or sublingually to variousmammalian species known to be subject to such maladies, e.g., humans, inan effective amount within the dosage range of about 0.2 to 1000 mg,preferably from about 1 to 100 mg in a regimen of single, two or fourdivided daily doses.

The compounds of the formula I can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such as inthe form of tablets, capsules, granules or powders; sublingually;bucally; parenterally, such as by subcutaneous, intravenous,intramuscular, or intracisternal injection or infusion techniques (e.g.,as sterile injectable aqueous or non-aqueous solutions or suspensions);nasally, including administration to the nasal membranes, such as byinhalation spray; topically, such as in the form of a cream or ointment;or rectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents. The present compounds can, for example, be administered ina form suitable for immediate release or extended release. Immediaterelease or extended release can be achieved by the use of suitablepharmaceutical compositions comprising the present compounds, or,particularly in the case of extended release, by the use of devices suchas subcutaneous implants or osmotic pumps. The present compounds canalso be administered liposomally.

Exemplary compositions for oral administration include suspensions whichcan contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which can contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The compounds of formula I can also be delivered through theoral cavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms which maybe used. Exemplary compositions include those formulating the presentcompound(s) with fast dissolving diluents such as mannitol, lactose,sucrose and/or cyclodextrins. Also included in such formulations may behigh molecular weight excipients such as celluloses (avicel) orpolyethylene glycols (PEG). Such formulations can also include anexcipient to aid mucosal adhesion such as hydroxy propyl cellulose(HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methylcellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agentsto control release such as polyacrylic copolymer (e.g. Carbopol 934).Lubricants, glidants, flavors, coloring agents and stabilizers may alsobe added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which can contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which can contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid, or Cremaphor.

Exemplary compositions for rectal administration include suppositorieswhich can contain, for example, a suitable non-irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquify and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

It will be understood that the specific dose level and frequency ofdosage for any particular subject can be varied and will depend upon avariety of factors including the activity of the specific compoundemployed, the metabolic stability and length of action of that compound,the species, age, body weight, general health, sex and diet of thesubject, the mode and time of administration, rate of excretion, drugcombination, and severity of the particular condition.

Pharmacological Analysis

The pharmacological analysis of each compound for either antagonism oragonism of 5-HT_(2A), 5-HT_(2B) and 5-HT_(2C) receptors consisted of invitro and in vivo studies. In vitro analyses included K_(i)determinations at 5-HT_(2A), 5-HT_(2B) and 5-HT_(2C) receptors and anassessment of functional (i.e., agonism or antagonism) activity at eachreceptor class by IP3 hydrolysis assays. Additional receptor assays wereconducted to evaluate receptor specificity of 5-HT_(2C) receptors overmonoamine and nuisance receptors (e.g. histamine, dopamine, andmuscarinic). A compound is considered active as a 5-HT₂ agonist if ithas an EC₅₀ value or a K_(i) value of less than about 50 micromolar;preferably less than about 1.0 micromolar; more preferably less thanabout 0.1 micromolar. Using the assays disclosed herein, compounds ofthe present application have been shown to have an EC₅₀ value of lessthan about 50 micromolar for 5-HT₂ agonism.

In vivo assays assessed compound activity in a variety of behavioralparadigms including acute and chronic feeding models, anxiety anddepression models (learned-helplessness, elevated plus maze,Geller-Siefter, conditioned taste aversion, taste reactivity, satietysequence). In aggregate, these models reflect activity as a 5-HT_(2C)agonist (feeding models, anxiety models, depression models) and providesome indication as to bioavailability, metabolism and pharmacokinetics.

Radioligand binding experiments were conducted on recombinant human5-HT_(2A), 5-HT_(2B), and 5-HT_(2C) receptors expressed in HEK293Ecells. The affinities of compounds of the present application to bind atthese receptors is determined by their capacity to compete for[¹²⁵I]-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane (DOI) or[³H]-lysergic acid diethylamide (LSD) binding at the 5-HT_(2A),5-HT_(2B), or 5-HT_(2C) receptors. General references for binding assaysinclude 1) Lucaites V L, Nelson D L, Wainscott D B, Baez M (1996)Receptor subtype and density determine the coupling repertoire of the5-HT₂ receptor subfamily. Life Sci., 59(13):1081-95. Glennon R A, SeggelM R, Soine W H, Herrick-Davis K, Lyon R A, Titeler M (1988)[125I]-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane: an iodinatedradioligand that specifically labels the agonist high-affinity state of5-HT2 serotonin receptors. J Med. Chem. (1988) 31(1):5-7 and 3 LeonhardtS, Gorospe E, Hoffman B J, Teitler M (1992) Molecular pharmacologicaldifferences in the interaction of serotonin with 5-hydroxytryptamine 1Cand 5-hydroxytryptamine2 receptors. Mol Pharmacol., 42(2):328-35.

The functional properties of compounds (efficacy and potency) weredetermined in whole cells expressing 5-HT_(2A), 5-HT_(2B), or 5-HT_(2C)receptors by assessing their ability to stimulate or inhibitreceptor-mediated phosphoinositol hydrolysis and/or intracellularcalcium release. The procedures used are described below.

In Vitro Binding Assays

Stable Expression of 5-HT_(2A), 5-HT_(2B) and 5-HT_(2C) Receptors inHEK293E Cells

Stable cell lines were generated by transfecting 293EBNA cells withplasmids containing human 5-HT_(2A), 5-HT_(2B), or 5-HT_(2C) receptor(INI, INV, VNV or VGV RNA-edited isoforms) cDNA using calcium phosphate.These plasmids also contained the cytomegalovirus (CMV) immediate earlypromoter to drive receptor expression and EBV oriP for their maintenanceas an extrachromosomal element, and the hph gene from E. coli to yieldhygromycin B resistance (Horlick et al., 1997). Transfected cells weremaintained in Dulbecco's Modified Eagle medium (DMEM) containingdialyzed 10% fetal bovine serum at 37° C. in a humid environment (5%CO₂) for 10 days. The 5-HT_(2A) cells were adapted to spinner culturefor bulk processing whereas it was necessary to maintain the other linesas adherent cultures. On the day of harvest, cells were washed inphosphate-buffered saline (PBS), counted, and stored at −80° C.

Membrane Preparation

On the day of assay, pellets of whole cells (containing approximately1×10⁸ cells) expressing the 5-HT_(2A), 5-HT_(2B) or 5-HT_(2C) receptorwere thawed on ice and homogenized in 50 mM Tris HCl (pH 7.7) containing1.0 mM EDTA using a Brinkman Polytron (PT-10, setting 6 for 10 sec). Thehomogenate was centrifuged at 48,000×g for 10 min and the resultingpellet washed twice by repeated homogenization and centrifugation steps.The final pellet was resuspended in tissue buffer and proteindeterminations were made by the bichichoninic acid (BCA) assay (PierceCo., Ill.) using bovine serum albumin as the standard.

Radioligand Binding Assays for the 5-HT_(2A), 5-HT_(2B) and 5-HT_(2C)Receptors

Radioligand binding studies were conducted to determine the bindingaffinities (Ki values) of compounds for the human recombinant 5-HT_(2A),5-HT_(2B), and 5-HT_(2C) receptors (Fitzgerald et al., 1999). Assayswere conducted in disposable polypropylene 96-well plates (Costar Corp.,Cambridge, Mass.) and were initiated by the addition of 5-HT_(2A),5-HT_(2B), or 5-HT_(2C) membrane homogenate in tissue buffer (10-30(g/well) to assay buffer (50 mM Tris HCl, 0.5 mM EDTA, 10 mM pargyline,10 mM MgSO₄, 0.05% ascorbic acid, pH 7.5) containing [¹²⁵I]DOI for the5-HT_(2A) and 5-HT_(2C) receptors (0.3-0.5 nM, final) or [³H]LSD (1-2.0nM, final) for the 5-HT_(2B) receptor, with or without competing drug(i.e, newly synthesized chemical entity). For a typical competitionexperiment, a fixed concentration of radioligand was competed withduplicate concentrations of ligand (12 concentrations ranging from 10picomolar to 10 micromolar). The reaction mixtures were incubated toequilibrium for 45 min at 37° C. and terminated by rapid filtration(Packard cell harvester; Perkin-Elmer) over GFB glass-fiber filters thathad been pre-soaked in 0.3% polyethyleneimine. Filters were washed inice-cold 50 mM Tris HCl buffer (pH 7.5) and then counted on a Top Count(Packard).

Phosphoinositide Hydrolysis Studies

The ability of newly synthesized compounds to stimulate phosphoinositide(PI) hydrolysis was monitored in whole cells using a variant (Egan etal., 1998) of a protocol described previously (Berridge et al., 1982).HEK293E cells expressing the human 5-HT_(2A), 5-HT_(2B), or 5-HT_(2C)receptor were lifted with 0.5 mM EDTA and plated at a density of100,000/well onto poly-D-lysine-coated 24-well plates (Biocoat; BectonDickinson, Bedford, Mass.) in Dulbecco's modified Eagle's serum (DMEM;Gibco BRL) containing high glucose, 2 mM glutamine, 10% dialyzed fetalcalf serum, 250 (g/ml hygromycin B, and 250 (g/ml G418. Following a24-48 hr period, the growth media was removed and replaced with DMEMwithout fetal calf serum and inositol (Gibco BRL). The cells were thenincubated with DMEM (without serum and inositol) containing a finalconcentration of 0.5 uCi/well myo-[³H]inositol for 16-18 hr. Followingthis incubation, the cells were washed with DMEM (without serum orinositol) containing 10 mM LiCl and 10 (M pargyline and then incubatedfor 30 min with the same media but now containing one of several testcompounds. Reactions were terminated by aspirating the media and lysingthe cells by freeze-thaw. [³H]phosphoinositides were extracted withchloroform/methanol (1:2 v/v), separated by anion exchangechromatography (Bio-Rad AGI-X8 resin), and counted by liquidscintillation spectroscopy as described previously (Egan et al., 1998).

Calcium Fluorescence Studies

The ability of newly synthesized compounds to stimulate calciumfluorescence was monitored in whole cells using a protocol describedpreviously (Fitzgerlad et al., 1999). HEK293E cells expressing the human5-HT_(2C), or 5-HT_(2B) receptor were lifted with 0.5 mM EDTA and platedat a density of 50,000/well onto poly-D-lysine-coated 96-well plates(Biocoat; Becton Dickinson, Bedford, Mass.) in Dulbecco's modifiedEagle's serum (DMEM; Gibco BRL) containing high glucose, 2 mM glutamine,10% dialyzed fetal calf serum, 250 μg/ml hygromycin B, and 250 μg/mlG418. Following a 24 hr period, the cell plates are removed from theincubator and an equal volume of Loading Buffer (Hanks BSS with 200 mMHEPES, pH 5.98) containing the calcium dye reagent (Fluo-3) is added toeach well (100 μL per well for 96-well plates and then incubated for 1hour at 37 C. Following the dye loading of the cells he plates aretransferred to the FLIPR. Test compounds are added to the plate as aconcentration response curve and the changes in fluorescence units dueto calcium influx are monitored for a period of three seconds.

Data Analyses

The equilibrium apparent dissociation constants (Ki's) from thecompetition experiments were calculated using an iterative nonlinearregression curve-fitting program (Excelfit and TA Activity Base). Forthe PI hydrolysis and FLIPR experiments, EC50's were calculated using aone-site ‘pseudo’ Hill model: y=((Rmax-Rmin)/(1+R/EC50)nH))+Rmax whereR=response (GraphPad Prism; San Diego, Calif.). Emax (maximal response)was derived from the fitted curve maxima (net IP stimulation) for eachcompound. Intrinsic activity (IA) was determined by expressing the Emaxof a compound as a percentage of the Emax of 5-HT (IA=1.0).

Efficacy Models to Evaluate Food Consumption and Weight Loss

Acute overnight feeding assay. Compounds are assessed to for theirability to reduce food consumption during the dark cycle, which is themost active period of feeding in the rat. Fischer 344 rats are trainedon a fixed ratio three (FR3) response paradigm which requires them topress a bar 3 consecutive times in order to obtain a food pellet. Thenumber of bar presses occurring throughout the dark cycle can bemonitored electronically as a measure of food intake by the animal. Ratsare dosed orally or intraperitoneally with test compound 30 minutesprior to the onset of the dark cycle. The treated animals are thenplaced in individual operant boxes for 15 hours (12 hrs of dark cycleand the first three hours of the light cycle). Food intake in compoundtreated animals is compared to that of vehicle treated animals in orderto determine percent reductions in food intake. Simultaneousmeasurements of water intake and locomotor activity are also measuredduring the period to assess for potential adverse effects.

Chronic Feeding Assay

Compounds are assessed for their long term impact on food intake andbody weight in a three to fourteen week chronic treatment paradigm inSprague-Dawley rats (starting weight ˜450 g). Male Sprague-Dawley ratsare pre-handled for one week prior to the onset of dosing during whichtime they are also assessed for food intake behavior. Rats are thenassigned to treatment groups. Rats are dosed with vehicle or compound byoral gavage. The food-intake and body weights are cumulatively assessedat the end of each treatment week and compared to vehicle treatedanimals. In some studies food intake is measured daily in order toassess the impact of reduced food consumption on pair-fed animals. Atthe end of the study period the animals are assessed for changes in bodycomposition utilizing DEXA and are then sacrificed in order to examinechanges in various blood plasma parameters.

REFERENCES

-   Arnt, J. Acta Pharmacol. et Toxicol. 1982: 51, 321-329.-   Berridge M. J., Downes P. C., Hanley M. R. (1982) Lithium amplifies    agonist-dependent phosphotidyinositol response in brain and salivary    glands. Biochem. J., 206, 587-595.-   Costall, B and Naylor, R J. Psychopharmacology. 1975: 43, 69-74.-   Egan C. T., Herrick-Davis K., Miller K., Glennon R. A., and    Teitler M. (1998) Agonist activity of LSD and lisuride at cloned    5-HT_(2A) and 5-HT_(2C) receptors. Psychopharmacology, 136, 409-414.-   Fitzgerald L. W., Conklin D. S., Krause C. M., Marshall A. P.,    Patterson J. P., Tran D. P., Iyer G., Kostich W. A., Largent B. L.,    Hartig P. R. (1999) High-affinity agonist binding correlates with    efficacy (intrinsic activity) at the human serotonin 5-HT_(2A) and    5-HT_(2C) receptors: evidence favoring the ternary complex and    two-state models of agonist action. J. Neurochem., 72, 2127-2134.-   Horlick, R. A., Sperle, K., Breth, L. A., Reid, C. C., Shen, E. S.,    Robbinds, A. K., Cooke, G. M., Largent, B. L. (1997) Rapid    Generation of stable cell lines expressing corticotrophin-releasing    hormone receptor for drug discovery. Protein Expr. Purif. 9,    301-308.

Dosage and Formulations

The serotonin agonist and serotonin antagonist compounds of thisapplication can be administered as treatment for the control orprevention of central nervous system disorders including obesity,anxiety, depression, psychosis, schizophrenia, sleep and sexualdisorders, migraine and other conditions associated with cephalic pain,social phobias, and gastrointestinal disorders such as dysfunction ofthe gastrointestinal tract motility by any means that produces-contactof the active agent with the agent's site of action, i.e., 5-HT2receptors, in the body of a mammal. It can be administered by anyconventional means available for use in conjunction withpharmaceuticals, either as an individual therapeutic agent or in acombination of therapeutic agents. It can be administered alone, butpreferably is administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice.

The compounds of the present application can be administered in suchoral dosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, theymay also be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form. Further, they mayalso be administered by internasal delivery, transdermal delivery andsuppository or depot delivery all using dosage forms well known to thoseof ordinary skill in the pharmaceutical arts.

The dosage administered will, of course, vary depending upon knownfactors, such as the pharmacodynamic characteristics of the particularagent and its mode and route of administration; the age, health andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; and the effectdesired. By way of general guidance, a daily dosage of active ingredientcan be expected to be about 0.001 to about 1000 milligrams per kilogramof body weight, with the preferred dose being about 0.01 to about 100mg/kg; with the more preferred dose being about 0.01 to about 30 mg/kg.Advantageously, compounds of the present application may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three, or four times daily.

Dosage forms of compositions suitable for administration contain fromabout 0.5 mg to about 100 mg of active ingredient per unit. In thesepharmaceutical compositions the active ingredient will ordinarily bepresent in an amount of about 0.5-95% by weight based on the totalweight of the composition. The active ingredient can be administeredorally in solid dosage forms, such as capsules, tablets and powders, orin liquid dosage forms, such as elixirs, syrups and suspensions. It canalso be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers,such as lactose, starch, cellulose derivatives, magnesium stearate,stearic acid, and the like. Similar diluents can be used to makecompressed tablets. Both tablets and capsules can be manufactured assustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract. Liquid dosage forms fororal administration can contain coloring and flavoring to increasepatient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and itssalts, and sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-parabenand chlorobutanol. Suitable pharmaceutical carriers are described inRemington's Pharmaceutical Sciences, supra, a standard reference text inthis field.

Useful pharmaceutical dosage-forms for administration of the compoundsof this application can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 mg of powdered activeingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg magnesiumstearic.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil can be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 mg of the active ingredient. The capsules should then bewashed and dried.

Tablets

A large number of tablets can be prepared by conventional procedures sothat the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg of starch and 98.8 mg of lactose.Appropriate coatings may be applied to increase palatability or delayabsorption.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 25 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mg of vanillin.

Injectable

A parenteral composition suitable for administration by injection can beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution is sterilized bycommonly used techniques.

EXAMPLES Example 1cis-3-Benzyl-6-bromo-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one

Step A. To a solution of 1,3-dibromobenzene (2.36 g, 10.0 mmol) in THF(20 mL) was added Mg (264 mg, 11.0 mmol) and 1,2-dibromoethane (8 μL) at20° C. The reaction mixture was stirred for 1 h at 20° C. to give(3-bromophenyl)magnesium bromide as a clear 0.5 M THF solution.

Step B. A 0.5 M THF solution of (3-bromophenyl)magnesium bromide (20 mL,10 mmol) was cooled to −15° C., and methyl1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate (1.05 g, 4.3 mmol) intoluene (3.0 mL) was slowly added for 3 h at −15° C. The reactionmixture was warmed to 20° C. and quenched by addition of saturated NH₄Claqueous solution followed by extraction with EtOAc. The combined organicsolution was dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was chromatographed in silica gel column (Hex/EtOAc 9/1) to givemethyl 1-benzyl-3-(3-bromophenyl)piperidine-4-carboxylate (1.0 g, 2.6mmol).

Step C. A mixture of methyl1-benzyl-3-(3-bromophenyl)piperidine-4-carboxylate (3.7 g, 9.5 mmol) andpolyphosphoric acid (37 g) was heated at 180° C. for 3 h then cooled to0.20° C. To the reaction mixture H₂O and saturated NH₄Cl aqueoussolution were added, successively then extracted with CH₂Cl₂. Thecombined organic solution was dried over MgSO₄, filtered andconcentrated in vacuo. The residue was chromatographed in silica gelcolumn (Hex/EtOAc 9/1) to obtain the title compound (631 mg, 1.8 mmol)MS (ES) 356.1 (M+H) along with the regio-isomer example 2 as the lesspolar fraction.

Example 2cis-3-Benzyl-8-bromo-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one

The title compound (608 mg, 1.7 mmol) was obtained from the step C ofexample 1 as the more polar fraction to the region-isomer example 1: MS(ES) 356.1 (M+H).

Example 3cis-3-Benzyl-6-(2,4-dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one

(280 mg, 0.79 mmol), 2,4-dichlorophenylboronic acid (181 mg, 0.95 mmol),barium hydroxide octahydrate (374 mg, 1.2 mmol) and triphenylphosphine(21 mg, 0.079 mmol) were dissolved in DMF (6.0 mL)/H₂O (1.2 mL), and thesolution was degassed. To the solution was added palladium(II) acetate(4.4 mg, 0.020 mmol), and the reaction mixture was heated at 90° C. for15 h under Ar. The reaction mixture was cooled to 20° C. and dilutedwith CH₂Cl₂. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated in vacuo. The residue was chromatographed insilica gel column (Hex/EtOAc 7/3) to obtain the title compound (132 mg,0.31 mmol): MS (ES) 422.1 (M+H).

Example 4cis-6-(2,4-Dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one

Step A. To a solution ofcis-3-benzyl-6-(2,4-dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one(132 mg, 0.31 mmol) in MeOH (4.0 mL) was added Pd(OH)₂ (26 mg, 20 wt %).The reaction mixture was stirred at 20° C. for 15 h under H₂ atmosphere,filtered through celite and concentrated in vacuo to give the crudetitle compound.

Step B. The residue from the step A was dissolved in dioxane (2.0 mL),and di-t-butyl dicarbonate (132 mg, 0.6 mmol) and 1M NaOH (2.0 mL) wereadded. The reaction mixture was stirred at 20° C. for 2 h diluted withEt₂O and washed with brine. The organic layer was dried over MgSO₄,filtered and concentrated in vacuo. The residue was chromatographed insilica gel column (Hex/EtOAc 9/1) to obtainedcis-6-(2,4-dichloro-phenyl)-9-oxo-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylicacid tert-butyl ester.

Step C. To a solution of6-(2,4-dichloro-phenyl)-9-oxo-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylicacid tert-butyl ester in CH₂Cl₂ (3.2 mL) was added trifluoroacetic acid(0.8 mL). The reaction mixture was stirred for 2 h at 20° C. thenconcentrated in vacuo. The residue was basified with NH₄OH thenextracted with CH₂Cl₂. The organic layer was dried over MgSO₄, filteredand concentrated in vacuo to give the title compound (42 mg, 0.13 mmol):MS (ES) 332.1 (M+H).

Example 5cis-6-(2,4-Dichloro-phenyl)-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene

Step A. To a solution ofcis-6-(2,4-dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one(40 mg, 0.12 mmol) in trifluoroacetic acid (2.0 mL) was added Et₃SiH (62mg, 0.53 mmol). The reaction mixture was stirred at 20° C. for 15 h thenconcentrated in vacuo. The residue was basified with NH₄OH thenextracted with CH₂Cl₂. The organic layer was dried over MgSO₄, filteredand concentrated in vacuo to give the crude title compound.

Step B. The residue from the step A was dissolved in dioxane (1.0 mL),and di-t-butyl dicarbonate (50 mg, 0.23 mmol) and 1M NaOH (1.0 mL) wereadded. The reaction mixture was stirred at 20° C. for 2 h diluted withEt₂O and washed with brine. The organic layer was dried over MgSO₄,filtered and concentrated in vacuo. The residue was chromatographed insilica gel column (Hex/EtOAc 95/5) to obtainedcis-6-(2,4-dichloro-phenyl)-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylicacid tert-butyl ester.

Step C. To a solution ofcis-6-(2,4-dichloro-phenyl)-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylicacid tert-butyl ester in CH₂Cl₂-(1.6 mL) was added trifluoroacetic acid(0.4 mL). The reaction mixture was stirred for 2 h at 20° C. thenconcentrated in vacuo. The residue was basified with NH₄OH thenextracted with CH₂Cl₂. The organic layer was dried over MgSO₄, filteredand concentrated in vacuo to give the title compound (20 mg, 0.06 mmol):MS (ES) 318.1 (M+H).

Example 6cis-3-Benzyl-8-(2,4-dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one

The title compound (90 mg, 0.21 mmol) was prepared by following theprocedure of example 3 fromcis-3-benzyl-8-bromo-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one (172mg, 0.51 mmol), 2,4-dichlorophenylboronic acid (153 mg, 0.80 mmol),barium hydroxide octahydrate (317 mg, 1.0 mmol) and triphenylphosphine(18 mg, 0.067 mmol) and palladium(II) acetate (3.8 mg, 0.017 mmol) inDMF (6.0 mL)/H₂O (1.2 mL): MS (ES) 422.1 (M+H).

Example 7cis-8-(2,4-Dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one

The title compound was prepared as a white solid (69 mg, 0.21) byfollowing the procedure step A of example 4 fromcis-3-benzyl-8-(2,4-dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one (90 mg, 0.21 mmol) andPd(OH)₂ (18 mg, 20 wt %) in MeOH (3.0 mL): MS (ES) 332.1 (M+H).

Example 8cis-8-(2,4-Dichloro-phenyl)-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-9-ol

To a solution ofcis-8-(2,4-dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one(15 mg, 0.045 mmol) in MeOH (1.0 mL) was added NaBH₄ (1.7 mg, 0.45 mmol)at 20° C. The reaction mixture was stirred at 20° C. for 2 h, quenchedby addition of acetic acid then concentrated in vacuo. The residue wasbasified with NH₄OH then extracted with CH₂Cl₂. The organic layer wasdried over MgSO₄, filtered and concentrated in vacuo to give the titlecompound (10 mg, 0.030 mmol): MS (ES) 334.1 (M+H).

Example 9cis-8-(2,4-Dichloro-phenyl)-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene

The title compound was prepared as a white solid (22 mg, 0.069) byfollowing the procedures of example 5 fromcis-8-(2,4-dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one(51 mg, 0.15 mmol), Et₃SiH (79 mg, 0.68 mmol) and trifluoroacetic acid(175 mg, 1.5 mmol): MS (ES) 318.1 (M+H).

Example 10cis-3-Benzyl-6-bromo-8-methyl-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one

Step A. To a solution of 1,3-dibromo-5-methylbenzene (24.7 g, 99 mmol)in THF (20 μL) and toluene (20 mL) was added Mg (2.6 g, 109 mmol) and1,2-dibromoethane (5 μL) at 20° C. The reaction mixture was stirred for1 h at 20° C. to give (3-bromo-5-methyl-phenyl)magnesium bromide as aclear 2.5 M THF/toluene solution.

Step B. A 2.5 M THF/toluene solution of(3-bromo-5-methylphenyl)magnesium bromide (40 mL, 99 mmol) was cooled to−15° C., and methyl 1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate(9.85 g, 42.6 mmol) in benzene (17.5 mL) was slowly added for 3 h at−15° C. The reaction mixture was stirred additional 2 h at −15° C. andwarmed to 20° C. The reaction was quenched by addition of saturatedNH₄Cl aqueous solution followed by extraction with EtOAc. The combinedorganic solution was dried over MgSO₄, filtered and concentrated invacuo. The residue was chromatographed in silica gel column (Hex/EtOAc9/1) to give methyl1-benzyl-3-(3-bromo5-methyl-phenyl)piperidine-4-carboxylate (12.2 g,30.3 mmol).

Step C. A mixture of methyl1-benzyl-3-(3-bromo-5-methyl-phenyl)piperidine-4-carboxylate (12.2 g,30.3 mmol) from step B and polyphosphoric acid (124 g) was heated at180° C. for 3 h then cooled to 0.20° C. To the reaction mixture H₂O andsaturated NH₄Cl aqueous solution were added, successively then extractedwith EtOAc. The combined organic solution was dried over MgSO₄, filteredand concentrated in vacuo. The residue was chromatographed in silica gelcolumn (Hex/EtOAc 9/1) to obtain the title compound (760 mg, 2.1 mmol):MS (ES) 370.1 (M+H).

Example 11cis-3-Benzyl-8-bromo-6-methyl-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one

The title compound was also obtained from the step C of example 10 (762mg, 2.1 mmol): MS (ES) 370.1 (M+H).

Example 12cis-3-Benzyl-6-bromo-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene

To a solution ofcis-3-Benzyl-6-bromo-8-methyl-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one(1.5 g, 4.0 mmol) in trifluoroacetic acid (15 mL) was added Et₃SiH (10mL). The reaction mixture was stirred at 20° C. for 3 days thenconcentrated in vacuo. The residue was basified with NH₄OH thenextracted with EtOAc. The organic layer was dried over MgSO₄, filteredand concentrated in vacuo. The residue was chromatographed in silica gelcolumn (Hex/EtOAc 9/1) to give the title compound (440 mg, 1.23 mmol):MS (ES) 356.1 (M+H).

Example 13 cis-8-Methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene

To a solution ofcis-3-benzyl-6-bromo-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene(50 mg, 0.14 mmol) in MeOH (2.0 mL) was added Pd(OH)₂ (−10 mg, 20 wt %).The reaction mixture was stirred at 20° C. for 15 h under H₂ atmosphere,filtered through celite and concentrated in vacuo. The residue waschromatographed in silica gel column (Hex/EtOAc 1/1) to give the titlecompound (21 mg, 1.1 mmol): MS (ES) 188.1 (M+H).

Example 14cis-3-Benzyl-6-(2,4-dichloro-phenyl)-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene

The title compound (85 mg, 0.20 mmol) was prepared by following theprocedure of example 3 fromcis-3-benzyl-6-bromo-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene(107 mg, 0.30 mmol), 2,4-dichlorophenylboronic acid (69 mg, 0.36 mmol),barium hydroxide octahydrate (142 mg, 0.45 mmol) and triphenylphosphine(7.9 mg, 0.03 mmol) and palladium(II) acetate (1.7 mg, 0.0075 mmol) inDMF (3.0 mL)/H₂O (0.6 mL): MS (ES) 422.1 (M+H).

Example 15cis-3-Benzyl-6-(2-chloro-4-trifluoromethyl-phenyl)-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene

The title compound (27 mg, 0.06 mmol) was prepared by following theprocedure of example 3 fromcis-3-benzyl-6-bromo-8-methyl-2,3,4,4a,9,9a-hexahydro -1H-3-aza-fluorene(107 mg, 0.30 mmol), 2-dichloro-4-trifluoromethyl-phenylboronic acid (81mg, 0.36 mmol), barium hydroxide octahydrate (142 mg, 0.45 mmol) andtriphenylphosphine (7.9 mg, 0.03 mmol) and palladium(II) acetate (1.7mg, 0.0075 mmol) in DMF (3.0 mL)/H₂O (0.6 mL): MS (ES) 456.1 (M+H).

Example 16cis-8-Methyl-6-phenyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene

To a solution ofcis-3-benzyl-6-(2,4-dichloro-phenyl)-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene(85 mg, 0.20 mmol) in MeOH (3.0 mL) was added Pd(OH)₂ (17 mg, 20 wt %)and catalytic amount of acetic acid. The reaction mixture was stirred at20° C. for 3 days under H₂ atmosphere, filtered through celite andconcentrated in vacuo. The residue was chromatographed in silica gelcolumn (Hex/EtOAc 1/1) to give the title compound (22 mg, 0.084 mmol):MS (ES) 264.2 (M+H).

Example 17cis-3,8-Dimethyl-6-phenyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene

Step A. To a solution ofcis-8-methyl-6-phenyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene (22 mg,0.084) in CH₂Cl₂ was added Et₃N (43 mg, 0.42 mmol) followed by ethylchloroformate (18 mg, 0.17 mmol). The reaction mixture was stirred at20° C. for 2 h and concentrated in vacuo. The residue waschromatographed in silica gel column (Hex/EtOAc 9/1) to givecis-8-methyl-6-phenyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylicacid ethyl ester (20 mg, 0.060 mmol).

Step B. To a solution ofcis-8-methyl-6-phenyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylicacid ethyl ester (20 mg, 0.060 mmol) in THF (1.0 mL) was added LiAlH₄(4.5 mg, 0.12 mmol) under Ar. The reaction mixture was stirred at 20° C.for 2 h then refluxed for 4 h. The reaction was cooled to 20° C. andquenched by addition of H₂O and 1M NaOH. The quenched reaction mixturewas extracted with CH₂Cl₂. The combined organic solution was dried overMgSO₄, filtered and concentrated in vacuo. The residue waschromatographed in silica gel column (Hex/EtOAc 1/1) to obtain the titlecompound (10 mg, 0.036 mmol): MS (ES) 278.2 (M+H).

Example 18cis-6-(2-Chloro-4-trifluoromethyl-phenyl)-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene

To a solution ofcis-3-benzyl-6-(2-chloro-4-trifluoromethyl-phenyl)-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene(25 mg, 0.055 mmol) in MeOH (1.5 mL) was added Pd(OH)₂ (5.0 mg, 20 wt %)and catalytic amount of acetic acid. The reaction mixture was stirred at20° C. for 10 h under H₂ atmosphere, filtered through celite andconcentrated in vacuo. The residue was chromatographed in silica gelcolumn (CH₂Cl₂/MeOH 95/5) to give the title compound (16 mg, 0.044mmol): MS (ES) 366.1 (M+H).

Example 19cis-6-(2-Chloro-4-trifluoromethyl-phenyl)-3,8-dimethyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene

The title compound (8.0 mg, 0.021 mmol) was prepared by following theprocedure of example 17.cis-6-(2-Chloro-4-trifluoromethyl-phenyl)-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene(16 mg, 0.044 mmol) was reacted with ethyl chloroformate (9.6 mg, 0.088mmol) and Et₃N (22.3 mg, 0.22 mmol) in CH₂Cl₂ (0.5 mL) to givecis-6-(2-chloro-4-trifluoromethyl-phenyl)-8-methyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylicacid ethyl ester (12 mg, 0.027 mmol) which was reduced with LiAlH₄ (2.1mg, 0.055 mmol) in THF (1 mL): MS (ES) 380.1 (M+H).

Example 20 cis-3,8-Dimethyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene

The title compound (9.0 mg, 0.044 mmol) was prepared by following theprocedure of example 17.cis-8-Methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene (16 mg, 0.085mmol) was reacted with ethyl chloroformate (18.5 mg, 0.17 mmol) and Et₃N(43 mg, 0.43 mmol) in CH₂Cl₂ (0.5 mL) to givecis-8-methyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylic acidethyl ester (12 mg, 0.046 mmol) which was reduced with LiAlH4 (3.5 mg,0.093 mmol) in THF (1 mL): MS (ES) 202.2 (M+H).

Example 21 cis-6-Methyl-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one

To a solution of cis-3-benzyl-8-bromo-6-methyl-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one (50 mg, 0.14 mmol) in MeOH (3.0 mL) was addedPd(OH)₂ (10.0 mg, 20 wt %). The reaction mixture was stirred at 20° C.for 15 h under H₂ atmosphere, filtered through celite and concentratedin vacuo. The residue was chromatographed in silica gel column(CH₂Cl₂/MeOH 95/5) to give the title compound (20 mg, 0.099 mmol): MS(ES) 202.2 (M+H).

Example 22cis-Benzyl-(3,8-dimethyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-6-yl)-amine

Step A. To a solution of ethyl chloroformate (293 mg, 2.7 mmol) in THF(1.5 mL) was added a solution ofcis-3-benzyl-6-bromo-8-methyl-2,3,4,4a,9,9a-hexahydro -1H-3-aza-fluorene(320 mg, 0.90 mmol) in dry THF (1.5 mL) dropwise over 10 min at 0° C.The reaction mixture was warmed to 20° C., stirred for 15 h andconcentrated in vacuo. The residue was chromatographed in silica gelcolumn (Hex/EtOAc 7/3) to yieldcis-6-bromo-8-methyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylicacid ethyl ester (130 mg, 0.38 mmol).

Step B.cis-6-Bromo-8-methyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylicacid ethyl ester (68 mg, 0.2 mmol), benzylamine (64 mg, 0.6 mmol),NaOt-Bu (58 mg, 0.3 mmol) and (2-biphenyl)di-t-butylphosphine (11 mg,0.018 mmol) were dissolved in toluene (5.0 mL), and the solution wasdegassed. To the solution was addedtris(dibenzylideneacetone)dipalladium (11 mg, 0.006 mmol), and thereaction mixture was heated at 80° C. for 15 h under Ar. The reactionmixture was cooled to 20° C. and diluted with CH₂Cl₂. The organic layerwas washed with brine, dried over MgSO₄, filtered and concentrated invacuo. The residue was filtered through short silica gel column(Hex/EtOAc 7/3) to obtain crudecis-6-benzylamino-8-methyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylicacid ethyl ester (66 mg, 0.18 mmol)

Step C. The title compound (5.0 mg, 0.016 mmol) was prepared byfollowing the procedure of step B of example 17 from crudecis-6-benzylamino-8-methyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylicacid ethyl ester (66 mg, 0.18 mmol) and LiAlH4 (27 mg, 0.73 mmol) in THF(1 mL): MS (ES) 307.2 (M+H).

Example 233-Benzyl-6-bromo-8-methyl-2,3,4,9-tetrahydro-1H-3-aza-fluorene

To a solution ofcis-3-benzyl-6-bromo-8-methyl-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one(680 mg, 1.8 mmol) in ethylene glycol (9.0 mL) was added hydrazinehydrate (1.8 mL). The reaction mixture was heated at 120° C. for 2 h andat 180° C. for additional 15 h. The reaction was cooled to 20° C.,quenched by addition of brine and extracted with CH₂Cl₂. The organiclayer was washed with brine, dried over MgSO₄, filtered and concentratedin vacuo. The residue was chromatographed in silica gel column(hexane/EtOAc 9/1) to give the title compound (42 mg, 0.12 mmol): MS(ES) 354.1 (M+H).

While it is apparent that the embodiments of the application hereindisclosed are well suited to fulfill the objectives stated above, itwill be appreciated that numerous modifications and other embodimentsmay be implemented by those skilled in the art, and it is intended thatthe appended claims cover all such modifications and embodiments thatfall within the true spirit and scope of the present application.

A number of references have been cited and the entire disclosures ofwhich are incorporated herein by reference.

1. A compound, including all pharmaceutically acceptable salts,prodrugs, solvates and stereoisomers thereof according to Formula I:

wherein, b is a single bond or a double bond; R¹ is selected from thegroup consisting of H, C₁-C₄ alkyl substituted with 0-3 R⁹, C₃-C₇cycloalkyl substituted with 0-3 R⁹ and arylalkyl substituted with 0-3R⁹; R² is selected from the group consisting of H and C₁-C₄ alkyl; R³ isselected from the group consisting of H, hydroxy and C₁-C₄ alkylsubstituted with 0-3 R⁹; R^(3′) is selected from the group consisting ofH and C₁-C₄ alkyl substituted with 0-3 R⁹, optionally R³ and R^(3′) maybe taken together with the atom to which they are joined to form acarbonyl (C═O); R⁴, R⁵, R⁶ and R⁷ are independently selected from thegroup consisting of H, halo, —CF₃, —OCF₃, —CN, —NO₂, —SCF₃, —CF₂CF₃,—OR¹², —SR¹², —NR¹²R¹³, —C(O)H, —C(O)R¹²—NR¹⁴C(O)R¹²,—OC(O)R¹²—OC(O)OR¹², —S(O)R¹², —S(O)₂R¹², —S(O)NR¹²R¹³, —S(O)₂NR¹²R¹³,—NR¹⁴S(O)R¹², —NR¹²C(O)R¹⁵, —NR¹²C(O)OR¹⁵, —NR¹²C(O)NHR¹⁵, C₁₋₆ alkylsubstituted with 0-2 R⁸,C₂₋₆ alkenyl substituted with 0-2 R⁸, C₂₋₆alkynyl substituted with 0-2 R⁸, aryl substituted with 0-3 R³³, 5-10membered heterocyclyl containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-3 R³³, C₃₋₆cycloalkyl substituted with 0-2 R⁸ and C₃₋₁₀ carbocyclyl substitutedwith 0-3 R³³ optionally one of R⁴ and R⁵, R⁵ and R⁶ or R⁶ and R⁷ may betaken together to form a 5-10 membered carbocyclyl, a 5-10 memberedheterocyclyl, aryl or a 5-7 membered heteroaryl ring; R⁸ is selectedfrom the group consisting of halo, —CF₃, —OCF₃, —OH, —CN, —NO₂, —SCF₃,—CF₂CF₃, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl, —OR¹², —SR¹², —NR¹²R¹³, —C(O)H, —C(O)R¹², —C(O)NR¹²R¹³,—NR¹⁴C(O)R¹², —C(O)OR¹², —OC(O)R¹², —OC(O)OR¹², —S(O)R¹², —S(O)₂R¹²,—S(O)NR¹²R¹³, —S(O)₂NR¹²R¹³, —NR¹⁴S(O)R¹², —NR¹⁴S(O)₂R¹², —NR¹²C(O)R¹⁵,—NR¹²C(O)OR¹⁵, —NR¹²S(O)₂R¹⁵, —NR¹²C(O)NHR¹⁵, aryl substituted with 0-5R³³, C₃₋₆ cycloalkyl substituted with 0-3 R³³, and 5-10 memberedheterocyclic ring system containing from 1-4 heteroatoms selected fromthe group consisting of N, O, and S substituted with 0-3 R³³; R⁹, ateach occurrence, is independently selected from halo, C₁₋₃ haloalkyl,C₁₋₄ alkoxy, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl,R¹² is selected from the group consisting of H, C₁₋₆ alkyl substitutedwith 0-2 R^(12a), C₂₋₆ alkenyl substituted with 0-2 R^(12a), C₂₋₆alkynyl substituted with 0-2 R^(12a), C₃₋₆ cycloalkyl substituted with0-3 R³³, aryl substituted with 0-5 R³³ and 5-10 membered heterocyclicring system containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-3 R³³; R^(12a) is selectedfrom the group consisting of H, halo, —OH, —CN, —NO₂, —CO₂H, —SO₂R⁴⁵,—SOR⁴⁵, —SR⁴⁵, —NR⁴⁶ SO₂R⁴⁵, —NR⁴⁶ COR⁴⁵, —NR⁴⁶R⁴⁷, —SO₂NR⁴⁶,—CONR⁴⁶R⁴⁶, —OR⁴⁵, ═O, C₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenylsubstituted with 0-5R³³, C₃₋₁₀ carbocyclyl substituted with 0-3 R³³, and5-10 membered heterocyclic ring system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-3R³³; R¹³ is selected from the group consisting of H, C₁₋₄ alkyl, C₂₋₄alkenyl, and C₂₋₄ alkynyl; optionally R¹² and R¹³ may be taken togetherto form 5-6 membered ring optionally substituted with —O— or —N(R¹⁴)— oroptionally R¹² and R¹³ may be taken together to form a 9-10 memberedbicyclic heterocyclic ring system containing 1-3 heteroatoms selectedfrom the group consisting of N, O and S wherein the bicyclicheterocyclic ring system may be saturated, partially saturated orunsaturated and the bicyclic heterocyclic ring system is substitute with0-3 R¹⁶; R¹⁴ is selected from the group consisting of H and C₁₋₄ alkyl;R¹⁵ is selected from the group consisting of H, C₁₋₄ alkyl, C₂₋₄alkenyl, and C₂₋₄ alkynyl; R¹⁶, at each occurrence, is independentlyselected from H, OH, halo, CN, NO₂, CF₃, SO₂R⁴⁵, NR⁴⁶R⁴⁷, —C(═O)H, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₃ haloalkyl-oxy-,and C₁₋₃ alkyloxy; R³³ is selected from the group consisting of H, OH,halo, —CN, —NO₂, —CF₃, —OCF₃, —SO₂R⁴⁵, —S(═O)R⁴⁵, —SR⁴⁵, —NR⁴⁶R⁴⁷,—NHC(═O)R⁴⁵, —C(═O)NR⁴⁶R⁴⁶, —C(═O)H, —C(═O)R⁴⁵, —C(═O)OR⁴⁵, —OC(═O)R⁴⁵,—OR⁴⁵, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyloxy, C₃₋₆ cycloalkyl, phenyl, aryl substitutedwith 0-2 R³⁴, C₁₋₆ alkyl substituted with R³⁴ and C₂₋₆ alkenylsubstituted with R³⁴; R³⁴, at each occurrence, is independently selectedfrom OH, C₁₋₄ alkoxy, —SO₂R⁴⁵, —NR⁴⁶R⁴⁷, NR⁴⁶R⁴⁷C(═O)—, and (C₁₋₄alkyl)CO₂—; R⁴⁵ is C₁₋₄ alkyl; R⁴⁶, at each occurrence, is independentlyselected from H and C₁₋₄ alkyl; and R⁴⁷, at each occurrence, isindependently selected from H, C₁₋₄ alkyl, —C(═O)NH(C₁₋₄ alkyl),—SO₂(C₁₋₄ alkyl), —C(═O)O(C₁₋₄ alkyl), —C(═O)(C₁₋₄ alkyl) and —C(═O)H,with the following provisos: (a) when R³ is hydroxy, R^(3′) is not CH₃;(b) when R¹ is CH₃, none of R⁴, R⁵, R⁶ and R⁷ are CH₃; (c) when R¹ is H,R⁶ is not H or CH₃; (d) when R¹ is —CH₂CH₂—(C₆H₅), R⁶ is not H or CH₃;and (e) when R¹ is C₁₋₄ alkyl, R⁵ is not H or C₁₋₆ alkyl.
 2. Thecompound according to claim 1, wherein b is a single bond.
 3. Thecompound according to claim 2, wherein R² is H.
 4. The compoundaccording to claim 3, wherein R⁴, R⁵, R⁶ and R⁷ are independentlyselected from the group consisting of H, halo, —NR¹²R¹³, C₁₋₆ alkylsubstituted with 0-2 R⁸ and aryl substituted with 0-3 R³³.
 5. Thecompound according to claim 1, wherein the compound is:cis-3-Benzyl-6-bromo-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one;cis-3-Benzyl-8-bromo -1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one;cis-3-Benzyl-6-(2,4-dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one;cis-6-(2,4-Dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one;cis-6-(2,4-Dichloro-phenyl) -2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene;cis-3-Benzyl-8-(2,4-dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one;cis-8-(2,4-Dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one;cis-8-(2,4-Dichloro-phenyl)-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-9-ol;cis-8-(2,4-Dichloro-phenyl) -2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene;cis-3-Benzyl-6-bromo-8-methyl-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one;cis-3-Benzyl-8-bromo-6-methyl-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one;cis-3-Benzyl-6-bromo-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene;cis-8-Methyl-2,3,4,4a,9,9a-hexahydro -1H-3-aza-fluorene;cis-3-Benzyl-6-(2,4-dichloro-phenyl)-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene;cis-3-Benzyl-6-(2-chloro-4-trifluoromethyl-phenyl)-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene;cis-8-Methyl-6-phenyl -2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene;cis-3,8-Dimethyl-6-phenyl-2,3,4,4a,9,9a-hexahydro -1H-3-aza-fluorene;cis-6-(2-Chloro-4-trifluoromethyl-phenyl)-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene;cis-6-(2-Chloro-4-trifluoromethyl-phenyl)-3,8-dimethyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene;cis-3,8-Dimethyl -2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene;cis-6-Methyl-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one;cis-Benzyl-(3,8-dimethyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-6-yl)-amine; and3-Benzyl-6-bromo-8-methyl-2,3,4,9-tetrahydro-1H-3-aza-fluorene.
 6. Apharmaceutical composition, comprising: at least one compound accordingclaim 1; and at least one pharmaceutically acceptable carrier ordiluent.
 7. The pharmaceutical composition according to claim 6, furthercomprising: at least one additional therapeutic agent.
 8. A method oftreating various diseases, conditions and disorders such as, forexample, metabolic diseases, which includes but is not limited toobesity, diabetes, diabetic complications, atherosclerosis, impairedglucose tolerance and dyslipidemia; eating disorders; central nervoussystem diseases which includes but is not limited to, anxiety,depression, obsessive compulsive disorder, panic disorder, psychosis,schizophrenia, sleep disorder, sexual disorder and social phobias;cephalic pain; migraine; and gastrointestinal disorders by administeringto a mammal in need of treatment a therapeutically effective amount of anovel compound according to claim
 1. 9. The method according to claim 8,wherein the disease, condition or disorder is obesity.